The invention relates to a method of reducing unwanted hair growth in mammals.
A main function of mammalian hair is to provide environmental protection. However, that function has largely been lost in humans, in whom hair is kept or removed from various parts of the body essentially for cosmetic reasons. For example, it is generally preferred to have hair on the scalp but not on the face.
Various procedures have been employed to remove unwanted hair, including shaving, electrolysis, depilatory creams or lotions, waxing, plucking, and therapeutic antiandrogens. These conventional procedures generally have drawbacks associated with them. Shaving, for instance, can cause nicks and cuts, and can leave a perception of an increase in the rate of hair regrowth. Shaving also can leave an undesirable stubble. Electrolysis, on the other hand, can keep a treated area free of hair for prolonged periods of time, but can be expensive, painful, and sometimes leaves scarring. Depilatory creams, though very effective, typically are not recommended for frequent use due to their high irritancy potential. Waxing and plucking can cause pain, discomfort, and poor removal of short hair. Finally, antiandrogens--which have been used to treat female hirsutism--can have unwanted side effects.
It has previously been disclosed that the rate and character of hair growth can be altered by applying to the skin inhibitors of certain enzymes. These inhibitors include inhibitors of 5-alpha reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, gamma-glutamyl transpeptidase, and transglutaminase. See, for example, Breuer et al., U.S. Pat. No. 4,885,289; Shander, U.S. Pat. No. 4,720,489; Ahluwalia, U.S. Pat. No. 5,095,007; Ahluwalia et al., U.S. Pat. No. 5,096,911; Shander et al., U.S. Pat. No. 5,132,293; and Shander et al., U.S. Pat. No. 5,143,925.
Metabolism of glucose to acetyl-CoA is carried out by a series of enzymes, with some enzymes performing a more regulatory (i.e., rate limiting) role than others. The Figure illustrates the metabolic pathway for the conversion of glucose to acetyl-CoA.
Referring to the Figure, the first enzyme in the series is hexokinase, which converts glucose to glucose-6-phosphate. The enzyme phosphohexoseisomerase then converts the glucose-6-phosphate to fructose-6-phosphate, which in turn is converted by phosphofructokinase to fructose-1,6-diphosphate. The enzyme aldolase then converts the fructose-1,6-diphosphate to glyceraldehyde-3-phosphate, which in turn is converted by glyceraldehyde-3-P-dehydrogenase to 1,3-diphosphoglycerate. The enzyme phosphoglycerate kinase then converts the 1,3-diphosphoglycerate to 3-phosphoglycerate, which in turn is converted by the enzyme phosphoglyceromutase to 2-phosphoglycerate. The enzyme enolase then converts the 2-phosphoglycerate to phospho(enol)pyruvate, which in turn is converted by pyruvate kinase to pyruvate. Pyruvate, finally, is converted by pyruvate dehydrogenase to acetyl-CoA.
The conversion of glucose to acetyl-CoA occurs inside the cell. Thus, for the conversion to occur glucose must be transported into the cell. The metabolic pathway for the conversion of glucose to acetyl-CoA, as used herein, includes the transport of glucose into the cell.
It has now been found that unwanted mammalian (including human) hair growth--particularly androgen stimulated hair growth--can be reduced by applying to the skin a dermatologically acceptable composition including a compound that suppresses the metabolic pathway for the conversion of glucose to acetyl-CoA in an amount effective to reduce hair growth. The unwanted hair growth which is reduced may be normal hair growth, or hair growth that results from an abnormal or diseased condition.
Compounds that suppress the metabolic pathway for the conversion of glucose to acetyl-CoA include inhibitors of the enzymes involved in the metabolic pathway and inhibitors of glucose transport into the cell. Preferably, the metabolic pathway is suppressed using an inhibitor of hexokinase, phosphofructokinase, pyruvate dehydrogenase, or glucose transport.
Examples of inhibitors of hexokinase include 6-amino-6-deoxy-glucose, N-acetyl-.beta.-D-mannosamine, D-mannosamine, and N-.alpha.-(p-tosyl)-L-lysine chloromethyl ketone. See de Domenech, FEBS Letters 119: 174-76, 1980; and Johnson, Biochemistry 21: 2984-89, 1982.
Examples of inhibitors of phosphofructokinase include phosphoglycerate, quinone methides (e.g., taxodone, taxodione), .alpha.-methylene lactones (e.g., euparotin acetate eupacunin, vernolepin), argaric acid, quinaldic acid, and 5'-p-flurosuflonylbenzoyl adenosine. See Colombo, J. Biol. Chem., 250: 9404-12, 1975; Hanson, Science 163: 378-80, 1970; McCune, Biochem. J., 259: 925-27, 1989; and Mansour, Biochem. Biophys. Res. Commun., 81: 1370-76, 1978.
Examples of inhibitors of aldose include 5-keto-D-fructose and 5-keto-D-fructose-1,6-bisphosphate. See Avigad, Biochem. Biophys. Acta, 343: 330-40, 1974.
Examples of inhibitors of phosphoglycerate kinase include Mg-phosphoglycerate and 2,3-diphosphoglycerate. See Scopes, Methods in Enzymology, 90: 134-38, 1982; and Gunter, Methods in Enzymology, 90: 103-10, 1982.
Examples of inhibitors of enolase include 3(trans)-chlorophosphoenolpyruvate, 3(cis)-cyanophosphoenolpyruvate, D-tartronate semialdehyde phosphate, aminoenolpyruvate, D-glycidol phosphate, and L-glycidol phosphate. See Liu, Arch. Biochem. Biophys. 277: 143-48, 1990; Wirsching, Biochemistry 24: 7602-06, 1985; Spring, Biochemistry, 10: 4655-60, 1971; and Rose, J. Biol. Chem., 244: 6548-57, 1969.
Examples of inhibitors of pyruvate kinase include hydroxy-1-cyclopropanecarboxylic acid and D(-)3-phosphoglyceric acid. See O'Leary, Biochem. Biophys. Res. Commun. 100: 1320-25, 1981.
Examples of inhibitors of pyruvate dehydrogenase include glyoxylate, hydroxypyruvate, kynurenate, xanthurenate, .alpha.-cyano-4-hydroxycinnamic acid, bromopyruvic acid, and fluropyruvic acid. See Bisswanger, J. Biol. Chem. 256: 815-22, 1981; Furuta, Methods in Enzymology, 89: 414-20, 1982; Waymack, Arch. Biochem. Biophys., 194: 258-64, 1979; Lowe, Biochemistry, 23: 91-97, 1984; and Bisswanger, Biochem. Biophys. Res. Commun. 95: 513-19, 1980.
Examples of inhibitors of glucose transport include phloretin, 5-thio-D-glucose, 2-deoxyglucose, 2-deoxy-2-fluoro-D-glucose, 3-deoxyglucose, and 3-deoxy-3-fluoro-D-glucose. See Coe, Biochim Biophys Acta, 264: 319-27, 1972; and Taylor, ACS Symposium Series, 170th meeting of ACS, 99-116, 1975.
The hair growth reducing compound is incorporated in a non-toxic dermatologically acceptable topical composition which preferably includes a vehicle or carrier which is adapted to be spread upon the skin. Examples of suitable vehicles are acetone, alcohols, or a cream, lotion, or gel which can effectively deliver the active compound. One such vehicle is disclosed in co-pending application PCT/US93/0506A. In addition, a penetration enhancer may be added to the vehicle to further enhance the effectiveness of the formulation.
The concentration of the hair growth inhibiting compound in the composition may be varied over a wide range up to a saturated solution, preferably from 0.1% to 30% by weight or even more; the reduction of hair growth increases as the amount of compound applied increases per unit area of skin. The maximum amount effectively applied is limited only by the rate at which the hair growth inhibiting compound penetrates the skin. Generally, the effective amounts range from 10 to 3000 micrograms or more per square centimeter of skin.
The composition should be topically applied to a selected area of the body from which it is desired to reduce hair growth. For example, the composition can be applied to the face, particularly to the beard area of the face, i.e., the cheek, neck, upper lip, and chin. The composition can also be applied to the legs, arms, torso or armpits. The composition is particularly suitable for reducing the growth of unwanted hair in women suffering from hirsutism or other conditions. In humans, the composition should be applied once or twice a day, or even more frequently, for at least three months to achieve a perceived reduction in hair growth. Reduction in hair growth is demonstrated when the frequency or hair removal is reduced, or the subject perceives less hair on the treated site, or quantitatively, when the weight of hair removed by shaving (i.e., hair mass) is reduced.
Male intact Golden Syrian hamsters are considered acceptable models for human beard hair growth in that they display oval shaped flank organs, one on each side, each about 8 mm in major diameter, which grow thick black and coarse hair similar to human beard hair. These organs produce hair in response to androgens in the hamster. To evaluate the effectiveness of a composition including a hair growth reducing compound, the flank organs of each of a group of hamsters are depilated by applying a thioglycolate based chemical depilatory (Surgex); alternatively, hair were removed by shaving the flank organs prior to topical treatments. To one organ of each animal 10 .mu.l of vehicle alone once a day is applied, while to the other organ of each animal an equal amount of vehicle containing a hair growth reducing compound is applied. After thirteen applications (one application per day for five days a week), the flank organs are shaved and the amount of recovered hair (hair mass) from each is weighed. Percent-reduction of hair growth is calculated by subtracting the hair mass (mg) value of the test compound treated side from the hair mass value of the vehicle treated side; the delta value obtained is then divided by the hair mass value of the vehicle treated side, and the resultant number is multiplied by 100.
The above-described assay will be referred to herein as the "Golden Syrian hamster" assay. Preferred compositions provide an inhibition in hair growth of at least about 20%, more preferably at least about 40%, and most preferably at least about 60% when tested in the Golden Syrian hamster assay. A number of compositions were tested in the Golden Syrian hamster assay; the results are provided in the Table.
TABLE __________________________________________________________________________ Hair Mass (mg) .+-. SEM Compound Vehicle pH Treated Untreated % Inhibition __________________________________________________________________________ N-.alpha.-(p-Tosyl)-L-lysine chloromethyl ketone A 5.0 0.48 .+-. .11 2.34 .+-. .26 81 .+-. 4 Quinaldic Acid A 4.5 0.62 .+-. .08 2.10 .+-. .20 69 .+-. 4 Mannosamine A 6.0 0.71 .+-. .13 2.27 .+-. .22 68 .+-. 6 Phosphogylcolic acid B 3.0 0.57 .+-. .09 1.80 .+-. .28 66 .+-. 5 N-Acetyl-.beta.-D-mannosamine A 6.0 0.79 .+-. .15 2.32 .+-. .13 65 .+-. 7 Kynurenic acid A 8.0 0.98 .+-. .09 2.89 .+-. .28 64 .+-. 4 Xanthurenic acid C 8.5 1.26 .+-. .13 3.40 .+-. .16 59 .+-. 4 5'-p-Flurosuflonylbenzoyl adenosine A 7.0 0.74 .+-. .05 1.97 .+-. .24 60 .+-. 3 6-Amino-6-deoxy glucose A 8.0 0.77 .+-. .15 1.90 .+-. .18 59 .+-. 8 Bromopyruvic acid A 3.5 1.10 .+-. .11 2.75 .+-. .35 58 .+-. 6 Phenylpyruvic acid D 7.5 0.92 .+-. .21 1.95 .+-. .15 54 .+-. 10 Argaric acid E 4.0 0.97 .+-. .14 2.02 .+-. .19 52 .+-. 4 .alpha.-Cyano-4-hydroxycinnamic acid F 7.0 0.87 .+-. .34 1.64 .+-. .19 49 .+-. 17 5-Thio-D-glucose A 6.0 1.32 .+-. .20 2.53 .+-. .14 49 .+-. 6 3-Fluoropyruvic acid A 7.0 1.14 .+-. .09 2.00 .+-. .17 40 .+-. 5 2-Deoxyglucose A 5.0 0.96 .+-. .16 1.55 .+-. .18 38 .+-. 7 Phloretin G 7.0 1.34 .+-. .11 2.15 .+-. .14 35 .+-. 7 1-Hydroxy-1-cyclopropanecarboxylic acid A 6.0 1.80 .+-. .20 2.28 .+-. .12 22 .+-. 9 D(-)3-Phosphoglyceric acid H 4.5 2.27 .+-. .22 2.89 .+-. .12 21 .+-. 7 __________________________________________________________________________ All compounds were tested at a 10% concentration in the following carrier (vehicles), except for 5'-pfluorosulfonylbenzoyl adenosine, xanthurenic acid and phloretin which were at 4.4%, 7.5%, and 15.0% respectively. Vehicle A: 68% Water, 16% ethanol, 5% propylene glycol, 5% dipropylene glycol, 4% benzyl alcohol, and 2% propylene carbonate. Vehicle B: 80% Ethanol, 10% dipropylene glycol, and 10% water. Vehicle C: 95% Water, and 5% DMSO. Vehicle D: 80% Water, 10% ethanol, and 10% propylene glycol. Vehicle E: 50% DMSO, 40% ethanol, 8.75% water, 1% propylene glycol dipelargonate (Emerest 2388), and 0.25% propylene glycol. Vehicle F: 80% Ethanol, 17.5% water, 2% propylene glycol dipelargonate (Emerest 2388), and 0.5% propylene glycol. Vehicle G: 80% Ethanol, 10% propylene glycol, and 10% water. Vehicle H: 90% Water, and 10% propylene glycol.